Biopsy Reclassification Research Articles

Extended Followup and Risk Factors for Disease Reclassification in a Large Active Surveillance Cohort for Localized Prostate Cancer

Active surveillance to manage prostate cancer provides an alternative to immediate treatment in men with low risk prostate cancer. We report updated outcomes from a long-standing active surveillance cohort and factors associated with reclassification. We retrospectively reviewed data on all men enrolled in the active surveillance cohort at our institution with at least 6 months of followup between 1990 and 2013. Surveillance consisted of quarterly prostate specific antigen testing, repeat imaging with transrectal ultrasound at provider discretion and periodic repeat prostate biopsies. Factors associated with repeat biopsy reclassification and local treatment were determined by multivariate Cox proportional hazards regression. We also analyzed the association of prostate specific antigen density and outcomes stratified by prostate size. A total of 810 men who consented to participate in the research cohort were followed on active surveillance for a median of 60 months. Of these men 556 (69%) met strict criteria for active surveillance. Five-year overall survival was 98%, treatment-free survival was 60% and biopsy reclassification-free survival was 40%. There were no prostate cancer related deaths. On multivariate analysis prostate specific antigen density was positively associated with the risk of biopsy reclassification and treatment while the number of biopsies and time between biopsies were inversely associated with the 2 outcomes (each p <0.01). When stratified by prostate volume, prostate specific antigen density remained significantly associated with biopsy reclassification for all strata but prostate specific antigen density was only significantly associated with treatment in men with a smaller prostate. Significant prostate cancer related morbidity and mortality remained rare at intermediate followup. Prostate specific antigen density was independently associated with biopsy reclassification and treatment while on active surveillance.

Multiparametric magnetic resonance imaging (MRI) and active surveillance for prostate cancer: future directions

A growing body of data exists suggesting an important role of MRI in selecting men with prostate cancer for active surveillance (AS). In the present study, Park et al. 1 show that a suspicious lesion on MRI was independently predictive of adverse pathology after radical prostatectomy (RP). This finding supports existing data suggesting that suspicious lesions on MRI confer an increased risk of disease reclassification among men enrolled in AS 2. Indeed, in our institutional AS experience we found that men with a suspicious lesion on MRI were more likely to have biopsy reclassification with extended follow-up 3. While these data are provocative, much work remains to be done before the adoption of MRI as a standard screening tool for entry into AS for men with very low-risk prostate cancer. Introduction of functional sequence imaging into multiparametric MRI protocols has resulted in improved detection and characterisation of clinically localised prostate cancer. However, before widespread implementation into AS protocols can occur, increased rigor and standardisation in image interpretation is needed. As in the present study, 5-point Likert scales have become an increasingly popular method of quantifying a lesions likelihood of representing cancer 1. Still other authors have quantified a lesions level of suspicion using both weighted and non-weighted scoring systems based on the number of positive MRI sequences 3, 4. While useful for statistical analysis, these reporting methods are fraught with concerns of inter-observer variability and generalizability. Additionally, a recent report by Lee et al. 5 found that a simple measurement of lesion diameter on diffusion-weighted MRI was predictive of insignificant disease after RP. Combining the plethora of functional and morphological data obtained by multiparametric MRI into a standardised, reproducible tool will greatly facilitate implementation of MRI into current AS screening protocols. As a step in the right direction, Stamatakis et al. 4 recently generated a nomogram for predicting biopsy reclassification in men on AS after taking into consideration both functional and morphological characteristics of MRI lesions. Adding an additional layer of complexity, they also assessed the utility of calculated values, e.g. lesion density (lesion volume/prostate volume), in predicting biopsy reclassification. Briefly, their analysis showed that the number of lesions, lesion suspicion, and lesion density were predictive of biopsy reclassification. While nomogram validation and testing of its predictive value on pathological outcomes is needed, this represents a major advance in the standardised application of MRI to AS cohorts. Despite great strides in the application of multiparametric MRI to AS cohorts, a significant concern about the false-negative rate exists. Considering the present report, of the 35 men with no visible lesion on MRI, 14.3% men had unfavourable pathology after RP 1. This is similar to previous studies reporting disease reclassification rates of <18% 2, 6. These men with normal imaging and high-grade cancer highlight the importance of incorporating imaging and clinical data when selecting men for AS. Better defining the false-negative rate of multiparametric MRI, and effectively identifying men with a normal MRI and high-grade disease remain major challenges. Considering all of the available data, it is becoming increasingly clear that MRI has the potential for improving the identification of patients for whom AS would be safe. It is currently the practice at our institution to refer eligible men for multiparametric MRI before enrolment in AS. Our future scholarly efforts should be directed at the standardisation of reporting MRI data and the development of user-friendly AS criteria that synthesise MRI results with clinicopathological data. None declared.

MP46-09 INDICATIONS FOR INTERVENTION DURING ACTIVE SURVEILLANCE OF PROSTATE CANCER: A COMPARISON OF THE JOHNS HOPKINS AND PRIAS PROTOCOLS

You have accessJournal of UrologyProstate Cancer: Localized IV1 Apr 2014MP46-09 INDICATIONS FOR INTERVENTION DURING ACTIVE SURVEILLANCE OF PROSTATE CANCER: A COMPARISON OF THE JOHNS HOPKINS AND PRIAS PROTOCOLS Max Kates, Jeffrey Tosoian, Bruce Trock, Zhaoyong Feng, Ballentine Carter, and Alan Partin Max KatesMax Kates More articles by this author , Jeffrey TosoianJeffrey Tosoian More articles by this author , Bruce TrockBruce Trock More articles by this author , Zhaoyong FengZhaoyong Feng More articles by this author , Ballentine CarterBallentine Carter More articles by this author , and Alan PartinAlan Partin More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1442AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Active surveillance is an alternative to immediate intervention that may reduce overtreatment in men with low risk prostate cancer. The widespread acceptance of active surveillance, however, has been limited by a lack of consensus on criteria for monitoring and intervention. Two outstanding questions include the need for yearly biopsy and the use of PSA kinetics as a trigger for intervention. We analyzed how patients enrolled in our biopsy-based surveillance program would fare under the PRIAS protocol which utilizes PSA kinetics. Methods Since 1995, 1,125 men with favorable risk prostate cancer have enrolled in the AS program at Johns Hopkins Hospital. Entrance criteria include: clinical stage T1c, PSA density < 0.15 ng/mL, and prostate biopsy findings (Gleason score ¡Ü 6, ¡Ü 2 cores involved, ¡Ü 50% cancer involvement of any core). Surveillance protocol involves semi-annual PSA and annual biopsy, and pathological reclassification triggers definitive therapy. The PRIAS protocol obtains PSA measurement every 3 months and scheduled biopsies in years 1, 4, and 7. PSA doubling time triggers definitive therapy (if PSADT <3 yrs) or repeat biopsy (if PSADT 3-10 yrs). Patients enrolled in the JHH AS program were retrospectively reviewed to evaluate how the use of PRIAS protocol would alter the timing and identification for curative intervention. The primary outcome was pathological reclassification on prostate biopsy. Results Over follow-up time of 2.9 yrs, 427 (38%) men experienced biopsy reclassification. Of those, 260 (61%) were detected at biopsy intervals corresponding to PRIAS criteria (222 at 1 yr, 28 at 4 yrs, and 10 at 7 yrs). In 67 (16%) men, reclassification was detected between PRIAS biopsy years (55 at 2-3 yrs, 9 at 5-6 yrs, 3 after 7 yrs), with a median delay in detection of 1.9 yrs (range 0.1 ¨C 2.5 yrs). Of 204 men with >5 yrs of follow up without biopsy reclassification, 32 (16%) had PSADT <3 yrs that would have triggered immediate intervention under PRIAS, and 54 (26%) had PSADT 3-10 yrs that would have triggered biopsy. 22 (11%) men went on to be reclassified at a median of 4.7 yrs after their date of PSADT progression. Conclusions For patients enrolled in active surveillance, use of the PRIAS monitoring protocol would have delayed identification of biopsy reclassification in 16% of men with a median delay of 1.9 yrs as compared to an annual biopsy schedule. Progression based on PSA kinetics would result in over-treatment of 5% of men, while initiating earlier intervention (by median 4.7 yrs) in 11% of patients with eventual reclassification. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e513 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Max Kates More articles by this author Jeffrey Tosoian More articles by this author Bruce Trock More articles by this author Zhaoyong Feng More articles by this author Ballentine Carter More articles by this author Alan Partin More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Prostate Specific Antigen Velocity Risk Count Predicts Biopsy Reclassification for Men with Very Low Risk Prostate Cancer

Prostate specific antigen velocity is an unreliable predictor of adverse pathology findings in patients on active surveillance for low risk prostate cancer. However, to our knowledge a new concept called prostate specific antigen velocity risk count, recently validated in a screening cohort, has not been investigated in an active surveillance cohort. We evaluated a cohort of men from 1995 to 2012 with prostate cancer on active surveillance. They had stage T1c disease, prostate specific antigen density less than 0.15 ng/ml, Gleason score 6 or less, 2 or fewer biopsy cores and 50% or less involvement of any core with cancer. The men were observed by semiannual prostate specific antigen measurements, digital rectal examinations and an annual surveillance biopsy. Treatment was recommended for biopsy reclassification. Patients with 30 months or greater of followup and 3 serial prostate specific antigen velocity measurements were used in primary analysis by logistic regression, Cox proportional hazards, Kaplan-Meier analysis and performance parameters, including the AUC of the ROC curve. Primary analysis included 275 of 668 men who met very low risk inclusion criteria, of whom 83 (30.2%) were reclassified at a median of 57.1 months. Reclassification risk increased with risk count, that is a risk count of 3 (HR 4.63, 95% CI 1.54-13.87) and 2 (HR 3.73, 95% CI 1.75-7.97) compared to zero. Results were similar for Gleason score reclassification (HR 7.45, 95% CI 1.60-34.71 and 3.96, 95% CI 1.35-11.62, respectively). On secondary analysis the negative predictive value (risk count 1 or less) was 91.5% for reclassification in the next year. Adding the prostate specific antigen velocity risk count improved the AUC in a model including baseline prostate specific antigen density (0.7423 vs 0.6818, p = 0.025) and it outperformed the addition of overall prostate specific antigen velocity (0.7423 vs 0.6960, p = 0.037). Prostate specific antigen velocity risk count may be useful for monitoring patients on active surveillance and decreasing the frequency of biopsies needed in the long term.

Serum prostate‐specific antigen (PSA) concentration is positively associated with rate of disease reclassification on subsequent active surveillance prostate biopsy in men with low PSA density

To investigate the association between serum prostate-specific antigen (PSA) concentration at active surveillance (AS) entry and disease reclassification on subsequent AS biopsy ('biopsy reclassification') in men with low PSA density (PSAD). To investigate whether a clinically meaningful PSA threshold for AS eligibility/ineligibility for men with low PSAD can be identified based on risk of subsequent biopsy reclassification. We included men enrolled in the Johns Hopkins AS Study (JHAS) who had a PSAD of <0.15 ng/mL/g (640 men). We estimated the incidence rates (IRs; per 100 person years) and hazard ratios (HR) of biopsy reclassification (Gleason score ≥ 7, any Gleason pattern 4 or 5, ≥3 positive cores, or ≥50% cancer involvement/biopsy core) for categories of serum PSA concentration at the time of entry into AS. We generated predicted IRs using Poisson regression to adjust for age and prostate volume, mean percentage free PSA (ratio of free to total PSA) and maximum percentage biopsy core involvement with cancer. The unadjusted IRs (per 100 person years) of biopsy reclassification across serum PSA concentration at entry into JHAS showed, in general, an increase; however, the pattern was not linear with higher IRs in the group ≥ 4 to <6 ng/mL (14.2, 95% confidence interval [CI] 11.8-17.2%) when compared with ≥6 to <8 ng/mL (8.4, 95% CI 5.7-12.3%) but almost similar IRs when compared with the group ≥ 8 to <10 ng/mL (14.8, 95% CI 8.4-26.1%). The adjusted predicted IRs of reclassification showed a similar non-linear increase in IRs, whereby the rates around 4 ng/mL were similar to the rates around 10 ng/mL. Risk for biopsy reclassification increased non-linearly across PSA concentration in men with low PSAD, whereby no obvious clinically meaningful threshold could be identified. This information could be incorporated into decision-making for AS. However, longer follow-up times are needed to warrant final conclusions.

Prediction of reclassification at repeat biopsy with [-2]proPSA during active surveillance for low-risk prostate cancer: Prospective longitudinal analysis of a Japanese multicenter study cohort.

e16054 Background: Biomarkers that predict aggressiveness and tumor burden of prostate cancer are needed for patients who undergo AS. One of such candidates is [-2]proPSA. It has been reported that expression of [-2]proPSA is specific to prostate cancer and associated with grade and stage. The aim of this research is to evaluate the predictive ability of [-2]proPSA and its related parameters for the biopsy reclassification during AS. Methods: 13 institutions participated in the multi-center Japanese AS study (a prospective one-arm cohort study). 134 patients were enrolled in this study between January 2002 and December 2003. Inclusion criteria are as follows; (1) stage T1cN0M0, (2) age from 50 to 80, (3) serum PSA = 20 ng/ ml or less, (4) one or two positive cores per 6 to 12 systematic biopsy cores, (5) Gleason score = 6 or less and (6) maximum cancer involvement in positive core = 50% or less. We prospectively collected blood samples from patients who opted AS as an initial treatment. The serum samples were stocked frozen until testing. The patients who remained on AS for 1-year were recommended to undergo repeat biopsy. Reclassification was judged by a central pathologist who was also involved in the initial diagnosis at inclusion. Results: 67 patients underwent repeat biopsy at 1-year after AS. Biopsy reclassification was histopathologically found in 25 of 67 patients (37.3%). Table shows the patients’ backgrounds and the cutoff values of predictive variables at 90% and 80% sensitivity and specificity. p2PSA, %p2PSA and phi; (p2PSA/fPSA) × √(tPSA) levels at baseline and p2PSA and phi at 1-year after AS were significantly higher in the reclassification group than those in the non-reclassification group. At 90% sensitivity, the cutoff values of p2PSA, %p2PSA and phi at baseline were 12.52, 1.51 and 37.91 with a specificity of 23.81%, 26.19% and 26.19%, respectively. In both 90% and 80% sensitivity, p2PSA and its related parameters have higher specificity than PSA and its related parameters. Conclusions: [-2]proPSA and its related parameters could predict pathological reclassification in repeat biopsy during AS.

Multiparametric magnetic resonance imaging findings in men with low‐risk prostate cancer followed using active surveillance

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Up to 35% of men on active surveillance (AS) for clinically localized prostate cancer will experience biopsy reclassification during follow-up. Currently, annual prostate biopsy is recommended in AS programmes. Multiparametric MRI has shown promise in identifying men at risk for immediate reclassification at the time of entry into AS; however, the MRI characteristics of men already enrolled in AS who may be at low risk for disease reclassification have not been fully described. In the present study, we describe the MRI findings of a cohort of men enrolled within AS, with extended follow-up. Among these men, multiparametric MRI demonstrated excellent specificity (0.974) and negative predictive value (0.897) for the detection of pathological index lesions (determined on serial biopsies). These results suggest that men enrolled in AS with a non-suspicious MRI are unlikely to harbour an index cancerous lesion. To assess the performance of multiparametric magnetic resonance imaging (MRI) in identifying pathological-index (path-index) lesions, defined as cancer present in the same prostate sextant in two separate surveillance biopsies, in men followed within an active surveillance (AS) programme for low-risk prostate cancer (CaP) with extended follow-up. A total of 50 men, representing >215 person-years of follow-up in an AS programme, who were referred for prostate MRI were randomly chosen to have their images reviewed by a radiologist with expertise in prostate MRI, who was blinded to biopsy results. Index lesions on MRI were defined as a single suspicious lesion ≥10 mm or >2 lesions in a given prostate sextant. Lesions on MRI were considered suspicious if ≥2 abnormal parameters co-registered anatomically. Path-index lesions were defined as cancer present in a given prostate sextant on two separate biopsy sessions. Sensitivity and specificity were calculated to test the performance of MRI for identifying path-index lesions. Clinical and pathological features were compared between men with and without a MRI-index lesion. A total of 31 path-index and 13 MRI-index lesions were detected in 22 and 10 patients, respectively. Multiparametric MRI demonstrated excellent specificity and negative predictive value (0.974 and 0.897, respectively) for the detection of path-index lesions. Sensitivity (0.19) and positive predictive value (0.46) were considerably lower. Patients with an index lesion on MRI were younger and less likely to have met the 'Epstein' criteria for very low-risk CaP. Compared with men without an MRI lesion, a significant increase in biopsy reclassification was noted for men with a MRI lesion (40 vs 12.5%, P = 0.04). A non-suspicious MRI was highly correlated with a lack of path-index lesions in an AS population. Multiparametric MRI may be useful in both the selection and monitoring of patients undergoing AS.

Low Prostate-specific Antigen and No Gleason Score Upgrade Despite More Extensive Cancer During Active Surveillance Predicts Insignificant Prostate Cancer at Radical Prostatectomy

To identify parameters that predict insignificant prostate cancer in 67 radical prostatectomies after biopsy reclassification to worse disease on active surveillance. Parameters evaluated at diagnosis and at biopsy reclassification included serum prostate-specific antigen, prostate-specific antigen density, number of positive cores, maximum percent involvement of cancer per core, and any interval negative biopsies. Gleason upgrading at biopsy reclassification was also assessed to predict insignificant cancer. Mean time between diagnosis and radical prostatectomies was 30.3 months with a median of 3 biopsies (range 2-9). Nineteen of 67 (28.4%) had clinically insignificant cancer at radical prostatectomy. In the entire group, there were no variables significantly associated with insignificant cancer at radical prostatectomy. In a subgroup analysis of 37 patients without Gleason pattern 4/5 at biopsy reclassification, 16/37 (43.2%) showed insignificant cancer at radical prostatectomy. In this subgroup, prostate-specific antigen at diagnosis was significantly lower in men with insignificant cancer (3.7 ng/mL) vs significant cancer (5.4 ng/mL) (P = .0005). With prostate-specific antigen <4 ng/mL at diagnosis or at biopsy reclassification, 12/13 (92.3%) men showed insignificant cancer, whereas only 4/24 (16.7%) men with prostate-specific antigen >4 ng/mL both at diagnosis and at biopsy reclassification showed insignificant cancer. Most men with biopsy reclassification while on active surveillance have significant disease at radical prostatectomy, justifying their treatment. Low prostate-specific antigen at diagnosis or at biopsy reclassification can predict a high probability of insignificant cancer in the absence of Gleason pattern 4/5 on biopsy. These men may be candidates for continuing active surveillance.

Editorial Comment

Before the advent of testing for prostate-specific antigen (PSA), men presented with bone pain or palpable prostate nodules as the first sign of prostate cancer. Treatment was usually limited to hormonal therapy. For those fortunate men with localized disease, the preferred treatment was often radiation therapy, but this gradually gave way to radical prostatectomy (RP), especially for men with Gleason pattern ≤6 disease. Two decades of PSA testing have completely transformed this paradigm. The number of incident cases has more than doubled and most men now present with localized disease. For younger men, RP is the preferred treatment, but the rising number of men presenting with very low-volume, low-grade cancers has raised concerns about over-diagnosis and over-treatment. Rather than presenting with disease too late, they are presenting too early. Low Prostate-specific Antigen and No Gleason Score Upgrade Despite More Extensive Cancer During Active Surveillance Predicts Insignificant Prostate Cancer at Radical ProstatectomyUrologyVol. 80Issue 4PreviewTo identify parameters that predict insignificant prostate cancer in 67 radical prostatectomies after biopsy reclassification to worse disease on active surveillance. Full-Text PDF

Association of [−2]proPSA with Biopsy Reclassification During Active Surveillance for Prostate Cancer

Previous studies have suggested an association between [-2]proPSA expression and prostate cancer detection. Less is known about the usefulness of this marker in following patients with prostate cancer on active surveillance. Thus, we examined the relationship between [-2]proPSA and biopsy results in men enrolled in an active surveillance program. In 167 men from our institutional active surveillance program we used Cox proportional hazards models to examine the relationship between [-2]proPSA and annual surveillance biopsy results. The outcome of interest was biopsy reclassification (Gleason score 7 or greater, more than 2 positive biopsy cores or more than 50% involvement of any core with cancer). We also examined the association of biopsy results with total prostate specific antigen, %fPSA, [-2]proPSA/%fPSA and the Beckman Coulter Prostate Health Index phi ([-2]proPSA/free prostate specific antigen) × (total prostate specific antigen)(½)). While on active surveillance (median time from diagnosis 4.3 years), 63 (37.7%) men demonstrated biopsy reclassification based on the previously mentioned criteria, including 28 (16.7%) of whom had reclassification based on Gleason score upgrading (Gleason score 7 or greater). Baseline and longitudinal %fPSA, %[-2]proPSA, [-2]proPSA/%fPSA and phi measurements were significantly associated with biopsy reclassification, and %[-2]proPSA and phi provided the greatest predictive accuracy for high grade cancer. In men on active surveillance, measures based on [-2]proPSA such as phi appear to provide improved prediction of biopsy reclassification during followup. Additional validation is warranted to determine whether clinically useful thresholds can be defined, and to better characterize the role of %[-2]proPSA and phi in conjunction with other markers in monitoring patients enrolled in active surveillance.

173 PROGRESSION FREE SURVIVAL IS ASSOCIATED WITH AN INCREASING PERCENTAGE OF BENIGN BIOPSIES DURING ACTIVE SURVEILLANCE FOR LOW RISK PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Active surveillance is a management option for select men with low risk prostate cancer. However, cancer surveillance necessitates repeat transrectal biopsies which are associated with patient discomfort and potential significant morbidity. Decreasing biopsy frequency would have a major clinical and financial impact. The objective of this study is to assess the impact of multiple negative biopsies on future biopsy reclassification. METHODS: Men with prostate cancer enrolled in our institutional active surveillance program who met pathologic criteria for enrollment and had a subsequent negative biopsy were identified. Demographic and clinical data was compared between patients who did and did not experience biopsy reclassification during follow-up; defined as a Gleason score 6, 2 cores involvement, or 50% involvement of a given core. Multivariable logistic regression analysis was performed to determine independent predictors of biopsy reclassification and rates were calculated for men with 33%, 33% 50%, 50% -67%, and 67% of their biopsies interpreted as benign. Kaplan-Meier survival analysis was performed to predict 5and 10-year progression free survival rates among these 4 groups of men. RESULTS: A total of 528 men representing 53.2% of our surveillance population were included in the analysis. A total of 88 (16.7%) men experienced reclassification at a mean of 59.2 months. These men were less likely to meet the Epstein criteria for very low risk disease (71.6% vs. 80.9%, p 0.05), were less likely to have 2 negative biopsies (p 0.01), and had a lower percentage of their biopsies interpreted as benign (33% vs. 55%, p 0.01). On multivariable logistic regression a PSA 4ng/dL at diagnosis (OR: 3.23; 1.47 7.12) and 50% of benign biopsies (OR: 0.06; 0.03 0.13) were independently associated with reclassification. No man with 67% benign biopsies progressed. Kaplan-Meier 5and 10-year progression free survival estimates for men with 50% 67%, 33% 50%, and 33% benign biopsies were 96.35%/79.70%, 79.05%/52.7%, and 68.88%/21.78%, respectively (p 0.001). CONCLUSIONS: A clinically significant proportion of men with negative biopsies during surveillance will experience reclassification on prostate biopsy. However, this risk is decreased in men who have a high percentage of benign biopsies. Percentage of benign biopsies may be used in future guidelines to decrease biopsy frequency in men with low risk prostate cancer on surveillance.

Effect of treatment with 5‐α reductase inhibitors on progression in monitored men with favourable‐risk prostate cancer

What's known on the subject? and What does the study add? Finasteride (Proscar) and dutasteride (Avodart) are 5-α reductase inhibitors (5-ARIs) used to treat LUTS in men with benign prostatic enlargement. Because these drugs suppress androgens, the theory has been put forward that 5-ARIs might prevent the development of prostate cancer. Careful analysis of two randomized controlled trials, however, showed that, in the clinical setting, this was not the case, and that these drugs can increase the occurrence of more aggressive high-grade disease. Because of this, the U.S. Food and Drug Administration did not approve 5-ARIs for the primary prevention of prostate cancer and notified healthcare professionals about a change in the 'Warnings and Precautions' for these drugs. Interest remains among some for using 5-ARIs in men diagnosed with very low-risk prostate cancer to delay the progression from clinically indolent disease to clinically significant disease requiring treatment. The present study investigated whether 5-ARI use among men with very low-risk prostate cancer in an active surveillance (AS) programme would reduce the number of cancers reclassified to clinically significant disease on surveillance biopsy. Our results do not support the use of 5-ARIs for slowing or preventing cancer progression in men with low-risk prostate cancer, but do suggest that men with very low-risk prostate cancer who take 5-ARIs for LUTS are unlikely to be at increased risk for the development of high grade disease during AS. To determine whether 5-α reductase inhibitor (5-ARI) use delays cancer reclassification in an active surveillance (AS) cohort. We performed a retrospective study of 587 men enrolled in an AS programme, who had no history of 5-ARI use. Chi-squared and t-tests were used to compare characteristics of 5-ARI users and non-users. Univariable and multivariable proportional hazards models, treating 5-ARI use as a time-dependent covariate, were used to evaluate the influence of 5-ARIs on the risk of a subsequent biopsy no longer meeting criteria for continued AS (i.e. reclassification). 5-ARI use was initiated in 47 men while on AS. Men using 5-ARIs had larger prostates and higher PSA levels at diagnosis. During 5-ARI use, PSA levels and prostate volume deceased by mean values of 47% and 11%, respectively. Men using 5-ARIs had a mean of 2.5 surveillance biopsies while on the drug. Reclassification occurred in 17% of 5-ARI users compared with 31% of non-users (P = 0.04). Multivariable models (adjusting for age, α-blocker use, PSA level, %free PSA, PSA density, prostate volume and number/percent biopsy core involvement at diagnosis) showed nonsignificant risk reductions for reclassification in 5-ARI users as determined by either tumour extent (hazard ratio [HR] = 0.37 (95% confidence interval [CI] 0.12 to 1.13), P = 0.08) or grade (HR = 0.8 (95% CI 0.25-2.59), P = 0.7). Treatment with 5-ARIs did not significantly alter the outcome of biopsy reclassification by grade in men with very low-risk prostate cancer.

Active Surveillance Program for Prostate Cancer: An Update of the Johns Hopkins Experience

We assessed outcomes of men with prostate cancer enrolled in active surveillance. Since 1995, a total of 769 men diagnosed with prostate cancer have been followed prospectively (median follow-up, 2.7 years; range, 0.01 to 15.0 years) on active surveillance. Enrollment criteria were for very-low-risk cancers, defined by clinical stage (T1c), prostate-specific antigen density < 0.15 ng/mL, and prostate biopsy findings (Gleason score ≤ 6, two or fewer cores with cancer, and ≤ 50% cancer involvement of any core). Curative intervention was recommended on disease reclassification on the basis of biopsy criteria. The primary outcome was survival free of intervention, and secondary outcomes were rates of disease reclassification and exit from the program. Outcomes were compared between men who did and did not meet very-low-risk criteria. The median survival free of intervention was 6.5 years (range, 0.0 to 15.0 years) after diagnosis, and the proportions of men remaining free of intervention after 2, 5, and 10 years of follow-up were 81%, 59%, and 41%, respectively. Overall, 255 men (33.2%) underwent intervention at a median of 2.2 years (range, 0.6 to 10.2 years) after diagnosis; 188 men (73.7%) underwent intervention on the basis of disease reclassification on biopsy. The proportions of men who underwent curative intervention (P = .026) or had biopsy reclassification (P < .001) were significantly lower in men who met enrollment criteria than in those who did not. There were no prostate cancer deaths. For carefully selected men, active surveillance with curative intent appears to be a safe alternative to immediate intervention. Limiting surveillance to very-low-risk patients may reduce the frequency of adverse outcomes.

A Multicenter Study of [-2]Pro-Prostate Specific Antigen Combined With Prostate Specific Antigen and Free Prostate Specific Antigen for Prostate Cancer Detection in the 2.0 to 10.0 ng/ml Prostate Specific Antigen Range

Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen(1/2)) to enhance specificity to detect overall and high grade prostate cancer. We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater + 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity.

-2]Proenzyme Prostate Specific Antigen is More Accurate Than Total and Free Prostate Specific Antigen in Differentiating Prostate Cancer From Benign Disease in a Prospective Prostate Cancer Screening Study

Due to the limited specificity of prostate specific antigen for prostate cancer screening, there is an ongoing search for adjunctive biomarkers. Retrospective studies have suggested that an isoform of proenzyme prostate specific antigen called [-2]proenzyme prostate specific antigen may enhance the specificity of prostate specific antigen based screening. We examined the usefulness of this isoform in a prospective prostate cancer screening study. From a population of 2,034 men undergoing prostate cancer screening we examined the relationship between the measurement of the [-2]isoform of proenzyme prostate specific antigen (p2PSA) and prostate cancer detection. Specifically we compared the usefulness of total prostate specific antigen, the ratio of free-to-total prostate specific antigen, the ratio of p2PSA-to-free prostate specific antigen, and a formula combining prostate specific antigen, free prostate specific antigen and p2PSA (the Beckman Coulter prostate health index or phi) to predict prostate cancer in men from the study undergoing prostate biopsy with a prostate specific antigen of 2.5 to 10 ng/ml and nonsuspicious digital rectal examination. Despite similar total prostate specific antigen (p = 0.88), percent free prostate specific antigen (p = 0.02) and %p2PSA (p = 0.0006) distinguished between positive and negative biopsy results. On ROC analysis %p2PSA (AUC 0.76) outperformed prostate specific antigen (AUC 0.50) and percent free prostate specific antigen (AUC 0.68) for differentiating between prostate cancer and benign disease. Setting the sensitivity at 88.5%, p2PSA led to a substantial improvement in specificity as well as positive and negative predictive values. The Beckman Coulter prostate health index (AUC 0.77) had the best overall performance characteristics. This is the first prospective study to our knowledge to demonstrate that p2PSA provides improved discrimination between prostate cancer and benign disease in screened men with a prostate specific antigen of 2.5 to 10 ng/ml and a negative digital rectal examination.

Factors Predicting Prostatic Biopsy Gleason Sum Under Grading

We determined clinical factors affecting the under grading of biopsy Gleason sum compared with prostatectomy pathology and developed a model predicting the probability of under grading. We analyzed a cohort of 1,701 patients treated for prostate cancer at our institution between 1988 and 2007 with complete biopsy and pathological data available. Patients with a biopsy Gleason sum of 7 or less were included in our analysis. Cases were categorized as under graded or not under graded by comparing biopsy and radical prostatectomy Gleason sums. Logistic regression was used to determine the predictors of under grading based on clinical variables (race, age at diagnosis, body mass index, prostate weight, diagnostic prostate specific antigen, biopsy positive-to-total core ratio, maximal cancer percent in positive cores and time from diagnosis to surgery). A nomogram was developed to calculate the probability of under grading. Results were validated using bootstrapping. Under grading occurred in 46.6% of our cohort. Significant variables predicting under grading were age at diagnosis, biopsy Gleason sum, diagnostic prostate specific antigen, prostate weight, biopsy positive-to-total core ratio and maximal percent of cancer in cores (p <0.05). Nomogram predictive accuracy was 72.4%. The risk of Gleason sum under grading can be predicted to a satisfactory level using our nomogram. Predicting under grading would improve patient consulting and identify those who should consider repeat biopsy, ultimately enhancing the accuracy of prostate cancer diagnosis.